Repurposing low–molecular-weight drugs against the main protease of severe acute respiratory syndrome coronavirus 2

Abstract

The coronavirus disease pandemic caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected the global healthcare system. Drug repurposing is a feasible method for emergency treatment. As low-molecular-weight drugs have high potential to completely match interactions with essential SARS-CoV-2 targets, we propose a strategy to identify such drugs using the fragment-based approach. Herein, using ligand-and protein-observed fragment screening approaches, we identified niacin and hit 1 binding to the catalytic pocket of the main protease of the SARS-CoV-2 (M pro ), thereby modestly inhibiting the enzymatic activity of M pro . Chemical shift perturbations induced by niacin and hit 1 indicate a partial overlap of their binding sites, i.e., the catalytic pocket of M pro may accommodate derivatives with large molecular sizes. Therefore, we searched for drugs containing niacin or hit 1 pharmacophores and identified carmofur, bendamustine, triclabendazole, and emedastine; these drugs are highly capable of inhibiting protease activity. Our study demonstrates that the fragment-based approach is a feasible strategy for identifying low-molecular-weight drugs against the SARS-CoV-2 and other potential targets lacking specific drugs.

Structural insights into the substrate‐binding site of main protease for the structure‐based COVID‐19 drug discovery

“…There are 141 different ligands in 194 crystal complexes, and the experimental binding affinities (IC 50 , K i , and K d values) have been reported only for 14 of the ligands. The other set contains 43 M pro inhibitors with experimental binding affinities but without complex structures which have been manually assembled and documented from the original papers 1,3,4,11,22,26,29–33 . See Table S7 for more information about the ligand names, experimental affinity data, and literature sources.…”

“…The other set contains 43 M pro inhibitors with experimental binding affinities but without complex structures which have been manually assembled and documented from the original papers. 1,3,4,11,22,26,[29][30][31][32][33] See Table S7 for more information about the ligand names, experimental affinity data, and literature sources.…”

“…The availability of crystallographic structural information and in vitro inhibitory activity data for the SARS‐CoV‐2 M pro are very essential to design and develop inhibitors for the protease. Fortunately, many high‐resolution crystal structures of the M pro in apo and holo states have been resolved and also, several experimental ligand‐binding affinity data have been reported for some different sets of promising inhibitors 1–4,11,22,26,29–33 . The valuable information has provided a golden opportunity for scientists and researchers to understand the molecular mechanisms of ligand‐protein interactions and currently, are being widely used for structure‐based drug discovery, drug repurposing, and high‐throughput screening studies 1,3,4,9,13,14,16,17,21,22,26,27,34–39 …”

“…Fortunately, many high-resolution crystal structures of the M pro in apo and holo states have been resolved and also, several experimental ligand-binding affinity data have been reported for some different sets of promising inhibitors. [1][2][3][4]11,22,26,[29][30][31][32][33] The valuable information has provided a golden opportunity for scientists and researchers to understand the molecular mechanisms of ligandprotein interactions and currently, are being widely used for structure-based drug discovery, drug repurposing, and highthroughput screening studies. 1,3,4,9,13,14,16,17,21,22,26,27,[34][35][36][37][38][39] In this study, we report a comprehensive comparative structural analysis of the M pro substrate binding site for both the unbound (apo) and ligand-bound (holo) states to identify key residues and conserved water molecules in the ligand-binding process.…”